Screening a large population in rural Pennsylvania for genes known to drive cancer led to early identification of medullary thyroid cancer (MTC) in 60 percent of patients who subsequently had a thyroidectomy (JAMA Otolaryngol Head Neck Surg 2023; doi:10.1001/jamaoto.2022.4195). Results suggest that large population genomic screening, such as MyCode launched in 2015 by the Geisinger Health System in central and northeastern Pennsylvania, could be used to detect the RET genetic variant that predisposes patients to MTC before any signs of disease become apparent to either patient or physician.
"Population genomic screening can identify patients at high risk for MTC prior to the development of clinical signs or symptoms of the disease, such as neck mass, concerning thyroid nodule, hoarseness, trouble breathing, or trouble swallowing," said Nicholas Purdy, DO, FACS, Director of Head and Neck Surgery in Geisinger's Department of Otolaryngology and lead author of the study.
Detecting the presence of a RET variant strongly suggests the use of genetic counseling, surveillance, and early treatment such as thyroidectomy to mitigate or wipe out any sign of thyroid tumor growth before it can spread to other parts of the body, according to the researchers.
"While additional data are needed to shape recommendations in individuals identified via population screening, given the high rate of occult MTC in this cohort, early surgical intervention should be considered in all patients found to have a P/LP [pathogenic/likely pathogenic] RET variant," Purdy and team wrote in their research.
Traditionally, treatment of patients with suspected thyroid cancer is prompted by the discovery of nodules in the thyroid gland or neck mass, followed by a thyroid ultrasound for all nodules and a fine-needle biopsy. If MTC is identified, American Thyroid Association guidelines recommend a complete workup, including germline testing for the RET gene.
By contrast, population-based genomic sequencing programs provide an opportunity to broadly identify patients with a genetic predisposition to disease with a goal of providing early clinical intervention that can reduce disease risk and save lives.
In MyCode, patient participants are asked to provide blood samples for DNA sequencing for a variety of medically actionable diseases. Results are subsequently disclosed to both primary care physicians and their patients. Along with the variant, physicians and patients are provided information regarding risks and recommended treatment.
Study Details
For this study, researchers sought to evaluate the clinical treatment and patient outcomes for those testing positive for the P/LP RET oncogene variant in the MyCode cohort of about 184,000 participants. The initial population included adults (age 18 and over) whose RET variant was disclosed between June 1, 2016, and May 31, 2022. Disclosure of results takes place through a Genetic Screening and Counseling Program via telephone, patient portal, or certified letter.
As of May 31, 2022, the variant had been disclosed to 85 adult patients; 10 of those patients who knew they carried the RET gene prior to the analysis were excluded from this study. Of the remaining 75 patients, 20 underwent total thyroidectomy (11 women and 9 men, median age 48 years). Sixty-five percent of these patients also had a central neck dissection. No patients had clinically apparent disease at the time of surgery.
Pathological findings indicated MTC for 12 of the 20 patients who underwent surgery to remove their thyroid gland (60%); papillary thyroid carcinomas were detected in two of the patients. In the patients with MTC, 10 had Stage I disease, one had Stage II disease, one had Stage III disease, and zero had Stage IV disease. According to surveillance imaging after surgery, along with laboratory values, no patient had evidence of recalcitrant disease during a mean follow-up of 22.4 months.
Though the results demonstrated that population genomic screening for MTC was effective, the researchers were a bit surprised by the small number of patients carrying the RET variant who did not undergo thyroidectomy, a standard recommendation for adults with the RET variant. In some cases, some patients were not able to be contacted via phone calls or letters, so they remained unaware of the test results; the researchers noted this as one potential explanation.
"We also feel that patients may be hesitant to act on a problem without symptoms or other signs of disease," Purdy said in an interview. "They might also have other health problems they perceive as more urgent to act on."
Among lessons learned from the study, Purdy said that "clear communication with patients and informed decision-making are vital to proper care of patients in our genetic testing program. We are learning the value of a multidisciplinary approach to care of these patients. Collaboration among genetic counselors, primary care physicians, endocrinologists, and surgeons is essential."
Next steps include establishing a protocol for patients who did not have a thyroidectomy, such as re-contacting patients who did not have have the procedure after a surgical consultation.
In an invited commentary in the same issue of JAMA Otolaryngology-Head & Neck Surgery (2023; doi:10.1001/jamaoto.2022.4196), two physicians noted that, if people are not prepared to accept the risks of surgery to treat potential cancers, "then the role of genetic testing as a widespread benefit measure is suspect."
Louise Davies, MD, MS, Associate Professor at the Dartmouth Institute, and Peter Angelos, MD, PhD, the Linda Kohler Anderson Professor of Surgery at the University of Chicago, concluded that the data from this study underscores "the need for greater patient education of why genetic testing is being done and the implications for long-term benefit."
The duo further noted that "effective screening requires a detailed system to communicate results, such as used in the Geisinger system, and there must be resources available to treat the identified risks or diseases. Genetic screening could be a distraction if the benefits accrued from the screening are small compared with the costs in terms of patient time and adverse effects, health care worker attention, and dollars."
Asked to respond to this commentary, Purdy replied: "Given the rarity of hereditary medullary thyroid cancer, isolated RET testing of the entire population would be ineffective. However, when done as part of a larger genetic screening program, some of the adverse 'costs' are blunted. We need larger numbers to ascertain the true cost benefits ratio for these patients."
Warren Froelich is a contributing writer.